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The Presynaptic Ribbon Maintains Vesicle Populations at the Hair Cell Afferent Fiber Synapse Lars Becker Stanford University

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The Presynaptic Ribbon Maintains Vesicle Populations at the Hair Cell Afferent Fiber Synapse Lars Becker Stanford University Washington University School of Medicine Digital Commons@Becker Open Access Publications 2018 The presynaptic ribbon maintains vesicle populations at the hair cell afferent fiber synapse Lars Becker Stanford University Michael E. Schnee Stanford University Mamiko Niwa Stanford University Willy Sun National Institute of Deafness and Communicative Disorders Stephan Maxeiner Stanford University See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Becker, Lars; Schnee, Michael E.; Niwa, Mamiko; Sun, Willy; Maxeiner, Stephan; Talaei, Sara; Kachar, Bechara; Rutherford, Mark A.; and Ricci, Anthony J., ,"The presynaptic ribbon maintains vesicle populations at the hair cell afferent fiber synapse." Elife.7,. e30241. (2018). https://digitalcommons.wustl.edu/open_access_pubs/6549 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Lars Becker, Michael E. Schnee, Mamiko Niwa, Willy Sun, Stephan Maxeiner, Sara Talaei, Bechara Kachar, Mark A. Rutherford, and Anthony J. Ricci This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/6549 RESEARCH ARTICLE The presynaptic ribbon maintains vesicle populations at the hair cell afferent fiber synapse Lars Becker1, Michael E Schnee1, Mamiko Niwa1†, Willy Sun2, Stephan Maxeiner3‡, Sara Talaei1, Bechara Kachar2, Mark A Rutherford4, Anthony J Ricci1,3* 1Department of Otolaryngology, Stanford University, Stanford, United States; 2National Institute of Deafness and Communicative Disorders, United States; 3Molecular and Cellular Physiology, Stanford University, Stanford, United States; 4Department of Otolaryngology, Washington University, St. Louis, United States Abstract The ribbon is the structural hallmark of cochlear inner hair cell (IHC) afferent synapses, yet its role in information transfer to spiral ganglion neurons (SGNs) remains unclear. We investigated the ribbon’s contribution to IHC synapse formation and function using KO mice lacking RIBEYE. Despite loss of the entire ribbon structure, synapses retained their spatiotemporal development and KO mice had a mild hearing deficit. IHCs of KO had fewer synaptic vesicles and reduced exocytosis in response to brief depolarization; a high stimulus level rescued exocytosis in *For correspondence: [email protected] KO. SGNs exhibited a lack of sustained excitatory postsynaptic currents (EPSCs). We observed larger postsynaptic glutamate receptor plaques, potentially compensating for the reduced EPSC † Present address: Department rate in KO. Surprisingly, large-amplitude EPSCs were maintained in KO, while a small population of of Otolaryngology, Johns low-amplitude slower EPSCs was increased in number. The ribbon facilitates signal transduction at Hopkins University, Baltimore, physiological stimulus levels by retaining a larger residency pool of synaptic vesicles. United States; ‡Department of DOI: https://doi.org/10.7554/eLife.30241.001 Neuroanatomy, Institute for Anatomy and Cell Biology, Medical School Saarland University, Saarbru¨ cken, Germany Introduction The synaptic ribbon is an electron dense structure associated with presynaptic active zones at sen- Competing interests: The sory synapses in the retina, lateral line and inner ear organs. RIBEYE is the major protein associated authors declare that no with the ribbon (Zanazzi and Matthews, 2009).It consists of a unique amino-terminal A domain, competing interests exist. which forms the ribbon scaffold, and a carboxy-terminal B domain with lysophosphatidic acid acyl- Funding: See page 23 transferase activity, which is almost identical to CtBP2, a transcriptional co-repressor (Schmitz et al., Received: 07 July 2017 2000). The ribbon is anchored to the presynaptic membrane by Bassoon protein in mammalian IHCs Accepted: 19 December 2017 (Khimich et al., 2005) as well as in retinal photoreceptors and bipolar cells (Dick et al., 2001). Published: 12 January 2018 Although it is comprised predominantly of RIBEYE (Zenisek et al., 2004), the ribbon complex may associate with over 30 different synaptic proteins (Uthaiah and Hudspeth, 2010; Reviewing editor: Christine Petit, Institut Pasteur, France Kantardzhieva et al., 2012). IHCs respond to sound with graded receptor potentials that drive rapid and precise synaptic This is an open-access article, release, encoding intensity and timing information (Fuchs, 2005; Matthews and Fuchs, 2010). The free of all copyright, and may be ribbon is thought to sustain continuous encoding by tethering a pool of vesicles that replenishes the freely reproduced, distributed, local pool of docked and primed vesicles upon depletion. Other functions ascribed to the ribbon transmitted, modified, built upon, or otherwise used by include: regulating vesicle trafficking from the cytoplasm to the active zone and serving as a vesicle 2+ anyone for any lawful purpose. trap to bind freely diffusing vesicles, as a location for vesicle formation, as a physical barrier for Ca 2+ The work is made available under ensuring a high local Ca signal, and as a primary structural component of the synapse anchoring 2+ the Creative Commons CC0 Ca channels close to synaptic vesicle release sites (Parsons et al., 1994; Frank et al., 2010; public domain dedication. Graydon et al., 2011; Kantardzhieva et al., 2012). Becker et al. eLife 2018;7:e30241. DOI: https://doi.org/10.7554/eLife.30241 1 of 26 Research article Neuroscience Postsynaptic excitatory postsynaptic currents (EPSCs) at ribbon synapses range in amplitude by up to 20-fold. The smallest and largest EPSCs have similar kinetics, which together suggest the exis- tence of a mechanism to synchronize the release of multiple quanta (multivesicular release, MVR; [Glowatzki and Fuchs, 2002; Li et al., 2009; Schnee et al., 2013; Rudolph et al., 2015]). By hold- ing vesicles and voltage-gated Ca2+ channels at the active zone, the ribbon may support MVR, occurring through various mechanisms including: (i) coordinated fusion of multiple single vesicles, (ii) release of large pre-fused vesicles, (iii) rapid sequential fusion in which the first fusion event triggers fusion of additional vesicles, or (iv) some combination of these mechanisms (Matthews and Fuchs, 2010). Previous attempts to study ribbon function used genetic disruption of the anchoring protein Bas- soon or acute destruction of the ribbon by fluorophore-assisted light inactivation (FALI). These manipulations resulted in smaller vesicle pool size, calcium channel mislocalization, increased audi- tory thresholds, asynchrony in neural responses and reductions in both tonic and phasic responses (Snellman et al., 2011; Jing et al., 2013). However, neither of those manipulations were selective for the ribbon and so might be manifestations of accessory protein denaturing. Recently, manipulation of the gene encoding CtBP2/RIBEYE allowed for deletion of RIBEYE by removing the A-domain of ctbp2 to eliminate ribbons in mice, enabling a more precise examination of ribbon function. This mouse will be referred to as KO and the littermate controls as WT through- out the manuscript. Elimination of ribbons in the retina reduced phasic and tonic transmission and rendered release sites sensitive to the slow calcium buffer EGTA (Maxeiner et al., 2016). Here we present analysis of cochlear synaptic anatomy, hair cell and afferent fiber physiology and hearing function in the RIBEYE knockout mouse. Results are distinct from those in the retina and from a RIBEYE deletion in zebrafish (Lv et al., 2016), suggesting a more subtle function for the ribbon than previously assumed. Results IHC-sSpiral ganglia neuron (SGN) synapses are formed and maintained despite absence of the ribbon The inner ear structure of the KO was assessed first for the presence of synaptic ribbons and synap- ses (Maxeiner et al., 2016). Validating loss of hair cell ribbons was accomplished using immunohis- tochemistry for the RIBEYE B-domain (CtBP2). Anti-CtBP2 labelled the ribbons in wildtype (WT) but not in the KO animals (postnatal day 21, P21)(Figure 1A). Nuclear CtBP2 was still observed in both WT and KO (not shown) because the KO is specific to the RIBEYE A-domain. The nuclear staining served as a usful control for antibody function. Using antibodies to Homer for postsynaptic labeling and Bassoon for presynaptic labeling (Figure 1B,C), we quantified the number of puncta and determined whether puncta were juxtaposed as synaptic pairs (Figure 1I,J). Bassoon and Homer puncta were similar in number in WT and KO mice (Bassoon — 40 ± 15 in WT, 43 ± 12 in KO, p=0.76; Homer — 17 ± 3 for both WT and KO; WT — n = 20 mice, KO — n = 19 mice, p=0.64). The number of paired Homer and Bassoon puncta (Figure 1D) were similarly comparable: 14 ± 2 (n = 20) for WT and 13 ± 2 (n = 19) for KO IHCs (p=0.18), suggesting that synapses were formed and maintained in comparable numbers regardless of the presence of ribbons. The higher number of Bassoon puncta probably reflects its localization at efferent synapses. Figure 1—figure supplement 1 presents a lower-magnification image that illustrates the multiple roles of Bassoon at the auditory periphery. Bassoon is a major component of the presynaptic elements at the auditory periphery, including the efferent fibers and the hair
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